Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897)

Three-Dimensional Transesophageal Echocardiography for Perioperative Right Ventricular Assessment

In high-risk cardiac procedures, dynamic analysis of right ventricular (RV) performance is desirable, but the geometric complexity of the RV limits the applicability of current two-dimensional echocardiographic imaging techniques. This study aimed to evaluate the utility of three-dimensional transesophageal echocardiography (TEE) for the perioperative assessment of RV function and dimensions. Patients undergoing cardiac surgical procedures with complete TEE examinations were identified and reviewed according to current guidelines to exclude patients with significant coexisting valvular regurgitation. Full-volume, three-dimensional datasets were analyzed by two independent investigators using stand-alone software, and left ventricular and RV dimensions were recorded. Datasets from 50 patients undergoing cardiac surgical procedures were evaluated for this study. The mean RV volume was 111.7 mL (range, 37.5 to 349.7 mL) at end diastole and 67.6 mL (range, 25.5 to 274.4 mL) at end systole. Intraobserver reliability was 0.93 and 0.90 for end diastolic and 0.77 and 0.87 for end systolic volumes. The interobserver reliability for RV volumes was 0.83 at end diastole and 0.86 at end systole. The mean stroke volume was 43.6 mL (range, 12 to 111.2 mL) for the RV and 49.1 mL (range, 19.9 to 102.8 mL) for the left ventricle; the correlation coefficient between the two was 0.85. Three-dimensional TEE volumetric measurements were reproducible across a wide range of RV dimensions. As postulated by the continuity principle, stroke volume measurements between both ventricles correlated well, supporting the validity of this approach. Therefore, our work provides preliminary evidence that three-dimensional TEE offers reproducible information about RV function and size in the dynamic and complex perioperative setting of cardiac surgical procedures